Project Summary/Abstract The nuclear co-activator AIB1 is a member of the NCOA/SRC/p160 family and is known to be amplified and overexpressed breast cancer. AIB1 acts as a scaffolding protein to facilitate assembly of transcription factors, and thereby promotes the transcriptional activity of oncogenic factor such as ER, NF?B, and AP-1. We have previously shown AIB1 co-activation to be directly suppressed by the ANCO1 tumor suppressor, which is lost during breast cancer progression. As a result, AIB1 promotes proliferation and disease progression. Further, in breast cancer mouse models, tissue specific AIB1 knockout reduces disease incidence and delays tumorigenesis. AIB1 contains a N-terminal bHLH/PAS activation domain that reportedly interacts with TEAD, effector of the Hippo pathway. Though the interaction between the AIB1 and TEAD has been shown to be mediated by the bHLH/PAS domain of AIB1, the physiological effects of the protein-protein interaction are unclear. As both proteins are potently oncogenic, their mechanism of interaction in normal tissue, and the extent of the interaction in malignant tissue, may be of extreme consequence and explain the oncogenic role of AIB1. Compared to other transactivators of TEADs, little is known about the specific target gene expression that results from AIB1-TEAD interaction. We hypothesize that the AIB1 binds TEAD near the transactivation domain, cooperates with other co-activators and repressors, and recruits TEAD selectively to promoters of target genes. We aim to define a mechanism of interaction between AIB1 and TEAD (Aim 1A-C), understand perturbations in binding associated with breast cancer progression (Aim 1D), and profile the loci of AIB1-TEAD co-occupancy on the genome (Aim 2). Successful completion of these aims will elucidate the consequences of AIB1-TEAD interaction during breast cancer progression, as well as the loss of ANCO1 suppression.